Improvement of liquid fructose-induced adipose tissue insulin resistance by ginger treatment in rats is associated with suppression of adipose macrophage-related proinflammatory cytokines

Abstract

Adipose tissue insulin resistance (Adipo-IR) results in excessive release of free fatty acids from adipose tissue, which plays a key role in the development of "lipotoxicity." Therefore, amelioration of Adipo-IR may benefit the treatment of other metabolic abnormalities. Here we found that treatment with the alcoholic extract of ginger (50 mg/kg/day, by oral gavage) for five weeks attenuated liquid fructose-induced hyperinsulinemia and an increase in the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. More importantly, ginger reversed the increases in the Adipo-IR index and plasma nonesterified fatty acid concentrations during the oral glucose tolerance test assessment. Adipose gene/protein expression profiles revealed that ginger treatment suppressed CD68 and F4/80, two important macrophage accumulation markers. Consistently, the macrophage-associated cytokines tissue necrosis factor alpha and interleukin-6 were also downregulated. In contrast, insulin receptor substrate (IRS)-1, but not IRS-2, was upregulated. Moreover, monocyte chemotactic protein (MCP)-1 and its receptor chemokine (C-C motif) receptor-2 were also suppressed. Thus these results suggest that amelioration of fructose-induced Adipo-IR by ginger treatment in rats is associated with suppression of adipose macrophage-related proinflammatory cytokines.

Figure 1

Body weight (a), body weight gain (b), epididymal white adipose tissue (eWAT) weight (c), ratio of eWAT weight to body weight (d), adipocyte number (e) and adipocyte size (f) in water-control and fructose-pair-fed rats. The fructose control rats had free access to 10% fructose in their drinking of water over 5 weeks, while the consumption of fructose in the ginger-(20 or 50 mg/kg) treated (by gavage daily) rats was adjusted to that of the fructose-control rats. Data are means ± SEM (n = 6 each group).

Figure 2

Representative images showing histology of eWAT (hematoxylin and eosin staining) in water-control or fructose-pair-fed rats (a)–(d). The fructose-control rats had free access to 10% fructose in their drinking water over 5 weeks, while the consumption of fructose in the ginger-(20 or 50 mg/kg) treated (by gavage daily) rats was adjusted to that of the fructose-control rats.

Figure 3

Plasma glucose (a) and insulin (b) concentrations at the baseline (fasted) and HOMA-IR index (c) in water-control and fructose-pair-fed rats. The fructose-control rats had free access to 10% fructose in their drinking water, while the consumption of fructose in the ginger-(20 or 50 mg/kg) treated (by gavage daily) rats was adjusted to that of the fructose-control rats. The variables were determined at the end of week 4. Data are means ± SEM (n = 6 each group). *P < 0.05.

Figure 4

Plasma concentrations of glucose (a) and insulin (c) and their area under curve (AUC)s ((b) and (d)) during oral glucose tolerance test (OGTT, glucose: 2 g/kg) assessment in water-control and fructose-pair-fed rats. The fructose-control rats had free access to 10% fructose in their drinking water, while the consumption of fructose in the ginger-(20 and/or 50 mg/kg) treated (by gavage daily) rats was adjusted to that of the fructose-control rats. OGTT was performed at the end of week 4. Data are means ± SEM (n = 6 each group). *P < 0.05.

Figure 5

Plasma NEFA concentrations at the baseline (fasted) (a) and during oral glucose tolerance test (OGTT, glucose: 2 g/kg) assessment (c), the AUC of NEFA concentrations during OGTT (d), and the adipose tissue insulin resistance (Adipo-IR) index (b) in water-control and fructose-pair-fed rats. The fructose-control rats had free access to 10% fructose in their drinking of water, while the consumption of fructose in the ginger-(20 and/or 50 mg/kg) treated (by gavage daily) rats was adjusted to that of the fructose-control rats. OGTT was performed at the end of week 4. Data are means ± SEM (n = 6 each group). *P < 0.05.

Figure 6

Adipose mRNA expression of CD68 (a), F4/80 (b), tumor necrosis factor (TNF)-α (c), interleukin (IL)-6 (d), insulin receptor substrates (IRS)-1 (e) and IRS-2 (f), monocyte chemotactic protein (MCP)-1 (g), chemokine (C-C motif) receptor (CCR)-2 (h) in fructose-pair-fed rats. The fructose-control rats had free access to 10% fructose in their drinking water, while the consumption of fructose in the ginger-(50 mg/kg) treated (by gavage daily) rats was adjusted to that of the fructose-control rats over 5 weeks. mRNA was determined by real-time PCR and normalized to β-actin. Levels in fructose control rats were arbitrarily assigned a value of 1. Data are means ± SEM (n = 6 each group). *P < 0.05.

Figure 7

Adipose mRNA expression of carbohydrate-response-element-binding protein (ChREBP) (a), sterol-regulatory-element-binding protein (SREBP)-1c (b), fatty acid synthase (FAS) (c), acetyl-CoA carboxylase (ACC)-1 (d), stearoyl-CoA desaturase (SCD)-1 (e), peroxisome-proliferator-activated receptor (PPAR)-γ (f), adiponectin (g), and CD36 (h) in fructose-pair-fed rats. The fructose-control rats had free access to 10% fructose in their drinking water, while the consumption of fructose in the ginger-(50 mg/kg) treated (by gavage daily) rats was adjusted to that of the fructose-control rats over 5 weeks. mRNA was determined by real-time PCR and normalized to β-actin. Levels in fructose-control rats were arbitrarily assigned a value of 1. Data are means ± SEM (n = 6 each group). *P < 0.05.